Malignant transformation represents the phenotypic endpoint of successive genetic lesions that confer uncontrolled proliferation and survival, unlimited replicative potential, and invasive growth. Recent evidence has suggested that non-coding RNAs, in particular, microRNAs (miRNAs), are subjected to changes in gene structure and expression regulation in tumors. I identified a polycistronic miRNA cluster, mir17-92, as a target of chromosome 13q31 amplicon found in human B-cell lymphomas. In a mouse model for B-cell lymphoma, enforced mir17-92 expression cooperates with c-myc and accelerates tumor growth by repressing cell death. These findings provided some of the first functional evidence that changes in miRNAs could contribute to oncogenesis. The work described in this application continues my studies on the oncogenic effects of mir17-92 using both cell culture systems and animal tumor models. First, I propose to identify the oncogenic miRNA components within the mir17-92 cluster, and to dissect the molecular basis for the tumorigenic effects of mir17-92. Second, the effects of mir17-92 in tumor maintenance and therapy response will be investigated. Finally, combined expression studies, copy number studies and functional characterization will be applied to examine more broadly the miRNA pathways in the oncogenic and tumor suppressor network. These studies, if successful, will produce fundamental insights into the functions of miRNAs during tumor development and tumor maintenance, which can be applied for discovery of both diagnostic markers and therapeutic targets.